Therapies for tuberculosis and AIDS: myeloid-derived suppressor cells in focus

Abstract

The critical role of suppressive myeloid cells in immune regulation has come to the forefront in cancer research, with myeloid-derived suppressor cells (MDSCs) as a main oncology immunotherapeutic target. Recent improvement and standardization of criteria classifying tumor-induced MDSCs have led to unified descriptions and also promoted MDSC research in tuberculosis (TB) and AIDS. Despite convincing evidence on the induction of MDSCs by pathogen-derived molecules and inflammatory mediators in TB and AIDS, very little attention has been given to their therapeutic modulation or roles in vaccination in these diseases. Clinical manifestations in TB are consequences of complex host-pathogen interactions and are substantially affected by HIV infection. Here we summarize the current understanding and knowledge gaps regarding the role of MDSCs in HIV and Mycobacterium tuberculosis (co)infections. We discuss key scientific priorities to enable application of this knowledge to the development of novel strategies to improve vaccine efficacy and/or implementation of enhanced treatment approaches. Building on recent findings and potential for cross-fertilization between oncology and infection biology, we highlight current challenges and untapped opportunities for translating new advances in MDSC research into clinical applications for TB and AIDS.

Figure 1. A schematic view of TB MDSCs and tumor MDSCs within the cellular architecture of the typical granuloma or tumor microenvironment.

The figure compares MDSCs in (A) the solid TME and (B) the TB granuloma microenvironment. M. tuberculosis infects various innate immune cells including macrophages and neutrophils within the granuloma. Macrophages might polarize and differentiate to form foam and multinucleated cells, whose presence is most frequently at the center of mature TB granulomas. Other myeloid cells include DCs that together form the core of the granuloma. Recruited NK cells, B cells, and T cells, including Th1, Th2, and Th17 cells, Tregs, and CD8⁺ T cells, form the outer cuff, often surrounded by fibroblasts and a collagen matrix (extracellular matrix [ECM]). The type, combination, phenotypes, and arrival timing of immune cells influence pathogen containment and the trajectory of granuloma development. Immune cells produce a range of soluble effector molecules such as cytokines and chemokines. In this inflammatory environment, advanced granulomas develop hypoxia and necrosis, which are followed by tissue destruction. The presence of MDSCs has been reported in necrotic TB granulomas. Similar cellular constituents and crosstalk have been reported for the TME. Apart from malignant cells, the TME contains immune cells, including TAMs and TANs, DCs, NK cells, and T cells, often surrounded by the stroma of fibroblasts and ECM. Both tumor and immune cells produce inflammatory and suppressive signaling molecules such as growth factors, cytokines, chemokines, etc. Tumor-derived immunosuppressive mechanisms are well described, including the presence of MDSCs.

Figure 2. Drugs targeting MDSCs in cancer and tested in TB.

Various classes of compounds target three main biological processes linked to MDSCs in oncology, notably genesis, dynamics, and suppressive functions. Depicted drugs have reached clinical trials in patients with cancer and been validated for their effects on MDSCs. Few compounds have been tested in animal models of TB (gray boxes). The compounds in the lower gray box have been tested as immunotherapeutics in TB; however, their effects on MDSCs have not been evaluated.